1. Field of the Invention
This invention relates to materials and methods for preparing (1S,2S,3S)-2-[2-(1-ethoxycarbonyl-3-phenyl-propylamino)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid, which is commonly known as quinapril.
2. Discussion
Quinapril hydrochloride is the active pharmaceutical ingredient in ACCUPRIL® and ACCURETIC®, which are marketed by Pfizer Inc. for treating hypertension and congestive heart failure. Quinapril, and its principal metabolite, quinaprilat (quinapril diacid), are known inhibitors of angiotensin converting enzyme (ACE). ACE is a peptidyl dipetidase that catalyzes conversion of angiotensin I to the vasoconstrictor, angiotensin II. See e.g., U.S. Pat. No. 4,344,949 issued to Hoefle et al. (the '949 patent), and U.S. Pat. No. 4,761,479 issued to Goel et al. (the '479 patent). See also Klutchko et al., “Synthesis of Novel Angiotensin Converting Enzyme Inhibitor Quinapril and Related Compounds. A Divergence of Structure-Activity Relationships for Non-Sulfhydryl and Sulfhydryl Types,” J. Med. Chem. Vol. 29 p. 1553 (1986).
Processes for preparing quinapril and its hydrochloride salt include methods based on the '949 patent and on U.S. Pat. No. 4,686,295 issued to Youssefyeh et al. (the '295 patent). These processes include reacting (3S)-1,2,3,4-tetrahydro-iosoquinoline-3-carboxylic acid benzyl ester (THIQ benzyl ester), with (1S,2S)-2-(1-carboxy-ethylamino)-4-phenyl-butyric acid ethyl ester, or with (2S,4S)-2-(4-methyl-2,5-dioxo-oxazolidin-3-yl)4-phenyl-butyric acid ethyl ester, to yield (1S,2S,3S)-2-[2-(1-ethoxycarbonyl-3-phenyl-propylamino)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid benzyl ester, 
Both reactions are carried out in an aprotic solvent, such as methylene chloride. The reaction involving the N-substituted amino acid (Formula 3) includes the use of a coupling agent (e.g., dicyclohexylcarbodiimide) and a catalyst (e.g., N-hydroxybenzotriazole), whereas the reaction involving the N-carboxyanhydride (Formula 4) employs catalytic amounts of an acid.
Following treatment with a mixture of HCl and a solvent, the benzyl protecting group of Formula 5 is subsequently removed via Pd/C-catalyzed hydrogenolysis to yield upon workup, the hydrochloride salt of quinapril, 
The synthetic routes based on the '949 and '295 patents employ readily available starting materials (Formula 2-Formula 4), but suffer a 20% to 40% yield loss based on the limiting reactant. The yield loss has been attributed to intramolecular cyclization (aminolysis) of quinapril (Formula 1) or its benzyl ester (Formula 5) to a diketopiperazine. See G. Guo et al., “Physical Characteristics and Chemical Degradation of Amorphous Quinapril Hydrochloride,” J. Pharm. Sci. Vol. 89 p. 128 (2000). Diketopiperazine formation is accelerated at temperatures above about 45° C. and is thought to occur primarily during distillation to remove the hydrogenolysis solvent.
The present invention is directed to overcoming, or reducing the effects of, one or more of the problems described above.